The delivery of drugs through the skin provides many advantages; primarily, such a means of delivery is a comfortable, convenient and noninvasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniences--e.g., gastrointestinal irritation and the like--are eliminated as well. Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.
However, many drugs are not suitable for passive transdermal drug delivery because of their size, ionic charge characteristics and hydrophilicity. One method of overcoming this limitation in order to achieve transdermal administration of such drugs is the use of electrical current to actively transport drugs into the body through intact skin. The method of the invention relates to such an administration technique, i.e., to "electrotransport" or "iontophoretic" drug delivery.
Herein the terms "electrotransport", "iontophoresis", and "iontophoretic" are used to refer to the transdermal delivery of pharmaceutically active agents by means of an applied electromotive force to an agent-containing reservoir. The agent may be delivered by electromigration, electroporation, electroosmosis or any combination thereof. Electroosmosis has also been referred to as electrohydrokinesis, electroconvection, and electrically induced osmosis. In general, electroosmosis of a species into a tissue results from the migration of solvent in which the species is contained, as a result of the application of electromotive force to the therapeutic species reservoir, i.e., solvent flow induced by electromigration of other ionic species. During the electrotransport process, certain modifications or alterations of the skin may occur such as the formation of transiently existing pores in the skin, also referred to as "electroporation". Any electrically assisted transport of species enhanced by modifications or alterations to the body surface (e.g., formation of pores in the skin) are also included in the term "electrotransport" as used herein. Thus, as used herein, the terms "electrotransport", "iontophoresis" and "iontophoretic" refer to (1) the delivery of charged drugs or agents by electromigration, (2) the delivery of uncharged drugs or agents by the process of electroosmosis, (3) the delivery of charged or uncharged drugs by electroporation, (4) the delivery of charged drugs or agents by the combined processes of electromigration and electroosmosis, and/or (5) the delivery of a mixture of charged and uncharged drugs or agents by the combined processes of electromigration and electroosmosis.
Systems for delivering ionized drugs through the skin have been known for some time. British Patent Specification No. 410,009 (1934) describes an iontophoretic delivery device which overcame one of the disadvantages of the early devices, namely, the need to immobilize the patient near a source of electric current. The device was made by forming, from the electrodes and the material containing the drug to be delivered, a galvanic cell which itself produced the current necessary for iontophoretic delivery. This device allowed the patient to move around during drug delivery and thus required substantially less interference with the patient's daily activities than previous iontophoretic delivery systems.
In present electrotransport devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the drug is delivered into the body. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's skin, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery, and usually to circuitry capable of controlling current passing through the device. If the ionic substance to be driven into the body is positively charged, then the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve as the counter electrode, completing the circuit. If the ionic substance to be delivered is negatively charged, then the cathodic electrode will be the active electrode and the anodic electrode will be the counter electrode.
Existing electrotransport devices additionally require a reservoir or source of the pharmaceutically active agent which is to be delivered or introduced into the body. Such drug reservoirs are connected to the anode or the cathode of the electrotransport device to provide a fixed or renewable source of one or more desired species or agents.
Thus, an electrotransport device or system, with its donor and counter electrodes, may be thought of as an electrochemical cell having two electrodes, each electrode having an associated half cell reaction, between which electrical current flows. Electrical current flowing through the conductive (e.g., metal) portions of the circuit is carried by electrons (electronic conduction), while current flowing through the liquid-containing portions of the device (i.e., the drug reservoir in the donor electrode, the electrolyte reservoir in the counter electrode, and the patient's body) is carried by ions (ionic conduction). Current is transferred from the metal portions to the liquid phase by means of oxidation and reduction charge transfer reactions which typically occur at the interface between the metal portion (e.g., a metal electrode) and the liquid phase (e.g., the drug solution). A detailed description of the electrochemical oxidation and reduction charge transfer reactions of the type involved in electrically assisted drug transport can be found in electrochemistry texts such as J. S. Newman, Electrochemical Systems (Prentice Hall, 1973) and A. J. Bard and L. R. Faulkner, Electrochemical Methods, Fundamentals and Applications (John Wiley & Sons, 1980).
As electrical current flows through an electrotransport device, oxidation of a chemical species takes place at the anode while reduction of a chemical species takes place at the cathode. Both of these reactions generate a mobile ionic species with a charge state (i.e., + or -) like that of the drug in its ionic form. Such a mobile ionic species is referred to as a "competitive species" or a "competitive ion" because the species competes with the drug for delivery by electrotransport.
Many drugs exist in both free acid/base form and a salt form. For example, a base drug may exist in either free base form or in salt form, e.g., in the form of an acid addition salt. One example of a base drug is lidocaine. In free base form, lidocaine is an amine. Lidocaine is also available as a hydrochloride acid addition salt. Conversely, an acid drug may exist in either free acid form or in the form of a salt made by reacting the free acid with a base. One example of an acid drug is salicylic acid. This drug also exists as a salt, typically as sodium salicylate. In general, the salt form of a drug is preferred over the free acid or free base form for electrotransport delivery since the salt form generally has much better water solubility and water is the preferred liquid solvent for electrotransport delivery due to its excellent biocompatibility.
Although the salt forms of drugs are likely to have higher water solubility, the pH of an aqueous solution of the drug salt may not be optimal from the standpoint of transdermal drug flux. For example, human skin exhibits a degree of permselectivity to charged ions which is dependant upon the pH of the donor solution of an electrotransport device. For anodic donor reservoir solutions, transdermal electrotransport flux of a cationic species (i.e., a cationic drug) is optimized when the pH of the donor solution is about 6 to 9, and more preferably about 7.5 to 8.5. For cathodic donor reservoir solutions, transdermal electrotransport flux of an anionic species (i.e., an anionic drug) is optimized when the pH of the donor solution is about 3 to 6, and more preferably about 3.5 to 5.
A problem which arises with the addition of pH-altering species (e.g., an acid or a base) to the drug solution in an electrotransport device is that extraneous ions having the same charge (i.e., same sign charge) as the drug are introduced into the solution. These ions generally compete with the therapeutic agent ions for electrotransport through the body surface. For example, the addition of sodium hydroxide to raise the pH of a cationic drug-containing solution will introduce sodium ions into the solution which will compete with the cationic drug for delivery by electrotransport into the patient, and thereby makes the electrotransport delivery less efficient since it takes more electric current to deliver a set amount of drug, i.e., less drug is delivered per unit of electrical current applied by the device due to competing ions carrying the current as opposed to the drug ions. The sodium ions, in this context, are termed "competing ions". As used herein, the term "competing ions" refers to ionic species having the same sign charge as the agent to be delivered by electrotransport, and which may take the place of the agent and be delivered through the body surface in its place. Similarly, conventional buffering agents used to buffer the pH of a donor reservoir solution can likewise result in the addition of competing ions into the donor reservoir which results in lower efficiency electrotransport drug delivery.
The present invention is addressed to a method for adjusting the pH of a drug formulation before it is incorporated into an electrotransport drug delivery system. The pH of any particular drug formulation may be adjusted either upward or downward, as desired. In this way, the flux of the drug through the skin may be optimized, as may the stability of particular drug/polymer matrix compositions. In this regard, it has been found that partially or completely neutralized drug formulations can yield a higher transdermal flux than the corresponding drug salt formulation, particularly when the drug is a divalent or polyvalent species.
In contrast to prior methods used to adjust the pH of a donor solution prior to electrotransport drug delivery, the present technique does not involve introduction of extraneous ions into the electrotransport system which would compete with the therapeutic agent ions for electrotransport through the body surface. For example, with cationic drugs, partial or complete neutralization by admixture with potassium hydroxide, sodium hydroxide, or the like would result in the incorporation of potassium ions, sodium ions, or the like, into the drug formulation, species which would in turn compete with the cationic drug for electrotransport delivery. Such a method reduces the efficiency of drug delivery and possibly results in other problems as well.
Additionally, the present method enables one to avoid the introduction of extraneous materials into the system, as may be associated with resins or the ite. U.S. Pat. No. 4,915,685 to Petelenz et al., for example, calls for incorporation of an ion exchange resin directly into the drug reservoir of an electrotransport delivery system. It is well known that industrial grade resins contain a number of impurities, which would of course be undesirable in a pharmaceutical formulation or device. The present invention avoids introduction of impurities in this manner.
Finally, it should be noted that the method of the invention, in providing a pH-adjusted drug formulation for electrotransport delivery, also facilitates buffering of the drug-containing composition. That is, the drug formulation will resist changes in pH which result from the addition of hydroxide ions or protons thereto.